PROJECT SUMMARY/ABSTRACT Children who receive radiation therapy for brain tumors are at significant risk for cognitive effects of their disease and treatment (e.g., problems with attention, memory and processing speed) that negatively impact quality of life, including reduced academic and social attainment. Low grade gliomas account for 30 to 50% of childhood brain tumors and have high survival rates, with progression-free survival rates approximately 80% on long-term follow-up. With a growing survivor population, efforts to improve long-term cognitive outcomes become imperative. A primary goal of this research program is development of interventions that mitigate the impact of CNS-directed therapies on the quality of life of childhood cancer survivors. The vascular hypothesis of radiation injury suggests that the mechanism of radiation-induced injury is similar to small vessel disease as seen with vascular dementia, prompting interest in treatments for vascular dementia. Randomized placebo- controlled trials have shown memantine (a drug that blocks NMDA receptors for the neurotransmitter glutamate) improves cognition in patients with mild to moderate vascular dementia without concerning side effects. Further, memantine during radiotherapy for brain metastases in adults has been shown to be well tolerated with less cognitive declines over time relative to placebo. Studies with children with Attention Deficit Hyperactivity Disorder or autism spectrum disorders have shown memantine is safe with evidence for improved cognition. Importantly, there are no published studies of memantine in children undergoing treatment for brain tumors. It has become of paramount importance to determine whether we can preserve cognitive function of children treated for cancer by intervening prophylactically, before the emergence of late effects. Accordingly, the specific aims of this study are: 1) To estimate the rate of participation, medication adherence and completion of cognitive assessments in a study of memantine used as a neuroprotective agent in children undergoing radiotherapy for low grade glioma; 2) To estimate the magnitude of change in neurobehavioral outcomes (cognitive, social, quality of life, neurologic) associated with memantine; and 3) To evaluate the frequency and nature of memantine side effects. In order to investigate these aims, we propose to use a randomized, double-blind, placebo-controlled design with children between 6 and 21 years of age scheduled to undergo cranial radiation therapy for a low grade glioma. Participants will be randomized to either memantine (20 mg/d) or a matching placebo. During the 12 week medication phase, participants will receive weekly phone calls to assess medication adherence and side effects. At baseline, 6 weeks (end of radiation therapy) and 12 weeks (end of the memantine medication phase) additional side effect monitoring will take place using laboratory values, physical examination and completion of an ECG. At the same three time points, and one year later, participants will complete laboratory measures of cognitive function and participate in neurologic exams. We will recruit participants until 30 have completed the 12 week assessment time point.